Upregulation of CFTR Protects against Palmitate-Induced Endothelial Dysfunction by Enhancing Autophagic Flux.
Upregulation of CFTR Protects against Palmitate-Induced Endothelial Dysfunction by Enhancing Autophagic Flux.
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CFTR 的上调可通过增强自噬通量来防止棕榈酸酯诱导的内皮功能障碍。
DOI：
10.1155/2020/8345246
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发表时间：
2020
影响因子：
--
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Chen H;Chen W;Yao Y;Ye N;Hou N;Luo J
饱和游离脂肪酸（FFAs）在代谢症状中升高，导致内皮功能障碍。囊性纤维化跨膜调节因子（CFTR）在内皮细胞中功能性表达。CFTR在FFA诱导的内皮功能障碍中的作用尚不清楚。本研究旨在探讨CFTR对棕榈酸（PA-）诱导的内皮功能障碍的影响及其机制。我们发现，PA诱导的内皮功能障碍的特点是细胞活力下降，NO产生和线粒体膜电位的减少，损害的管形成，但增加的ROS产生和细胞凋亡。同时，PA降低CFTR蛋白表达。CFTR激动剂Forskolin上调CFTR蛋白表达并保护PA诱导的内皮功能障碍，而CFTR敲低则加重PA诱导的内皮功能障碍并减弱Forskolin的保护作用。此外，PA损害自噬流量，自噬流量抑制剂加重PA诱导的内皮细胞凋亡。CFTR上调显著恢复PA损伤的内皮细胞中的自噬通量，其参与增加Atg 16 L、Atg 12-Atg 5复合物、组织蛋白酶B和组织蛋白酶D的蛋白表达。相反，CFTR敲低显著抑制Forskolin对自噬通量和自噬调节蛋白表达的影响。我们的研究结果表明，CFTR上调通过改善自噬通量来保护PA诱导的内皮功能障碍，其潜在机制涉及增强由Atg 16 L-Atg 12-Atg 5复合物、组织蛋白酶B和组织蛋白酶D介导的自噬信号。CFTR可能作为一种新的药物靶点，用于以FFA升高为特征的心血管疾病的内皮保护。
Saturated free fatty acids (FFAs) elevate in metabolic symptom leading to endothelial dysfunction. Cystic fibrosis transmembrane regulator (CFTR) functionally expresses in endothelial cells. The role of CFTR in FFA-induced endothelial dysfunction remains unclear. This study is aimed at exploring the effects of CFTR on palmitate- (PA-) induced endothelial dysfunction and its underlying mechanisms. We found that PA-induced endothelial dysfunction is characterized by a decrease of cell viability, reduction of NO generation and mitochondrial membrane potential, impairment of the tube formation, but an increase of ROS generation and cell apoptosis. Simultaneously, PA decreased CFTR protein expression. CFTR agonist Forskolin upregulated CFTR protein expression and protected against PA-induced endothelial dysfunction, while CFTR knockdown exacerbated endothelial dysfunction induced by PA and blunted the protective effects of Forskolin. In addition, PA impaired autophagic flux, and autophagic flux inhibitors aggravated PA-induced endothelial apoptosis. CFTR upregulation significantly restored autophagic flux in PA-insulted endothelial cells, which was involved in increasing the protein expression of Atg16L, Atg12-Atg5 complex, cathepsin B, and cathepsin D. In contrast, CFTR knockdown significantly inhibited the effects of Forskolin on autophagic flux and the expression of the autophagy-regulated proteins. Our findings illustrate that CFTR upregulation protects against PA-induced endothelial dysfunction by improving autophagic flux and underlying mechanisms are involved in enhancing autophagic signaling mediated by the Atg16L-Atg12-Atg5 complex, cathepsin B, and cathepsin D. CFTR might serve as a novel drug target for endothelial protection in cardiovascular diseases with a characteristic of elevation of FFAs.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
Kv1.5 的抑制可防止棕榈酸酯和 2 型糖尿病小鼠诱导的内皮细胞凋亡。
影响因子：
6.1
作者：
Du, Jie-Yi;Yuan, Feng;Wang, Guan-Lei
通讯作者：
Wang, Guan-Lei
硫化氢调节线粒体形态以促进高葡萄糖和高棕榈酸下内皮细胞的线粒体自噬
影响因子：
5.3
作者：
Liu N;Wu J;Zhang L;Gao Z;Sun Y;Yu M;Zhao Y;Dong S;Lu F;Zhang W
通讯作者：
Zhang W
DOI：
10.3390/healthcare5020029
发表时间：
2017-06-21
期刊：
Healthcare (Basel, Switzerland)
影响因子：
--
作者：
Briggs MA;Petersen KS;Kris-Etherton PM
通讯作者：
Kris-Etherton PM
DOI：
10.1073/pnas.92.16.7560
发表时间：
1995-08-01
影响因子：
11.1
作者：
MCDONALD, RA;MATTHEWS, RP;MCKNIGHT, GS
通讯作者：
MCKNIGHT, GS